Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-28
2001-07-17
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S866000
Reexamination Certificate
active
06262076
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical composition for use in the treatment of diabetic neuropathy. In particular, the present invention relates to a pharmaceutical composition for use in the treatment of diabetic neuropathy caused by a microvascular circulatory disturbance.
The term “diabetic neuropathy” indicates a neuropathy caused by a chronic hyperglycemic condition. The diabetic neuropathy is roughly classified into groups of multiple neuropathy, autonomic neuropathy and single neuropathy. Diabetic neurosis usually indicates a symmetrical, distal, multiple neuropathy mainly causing sensory disturbance. Both multiple neuropathy and autonomic neuropathy are neuropathies characteristic of diabetics.
A cause for the diabetic neuropathies is a chronic hyperglycemic state. However, the mechanism of the crisis has not been fully elucidated yet. For the crisis mechanism of the neuropathy caused by hyperglycemia, there are two main theories, i.e. vascular dysfunction and disturbed metabolism.
According to the vascular dysfunction theory, the blood flow is disturbed by changes of the blood abnormalities (such as acceleration of platelet aggregation, increase of the blood viscosity and decrease of the red blood-cell deformity) or by changes of the blood vessel abnormalities (such as reduction of the production of nitric oxide from the endothelial cells of blood vessels and acceleration of the reactivity on vasoconstrictive substances), then the hypoxia of nerves is caused, and finally the nerves are degenerated. For example, when the platelet aggregation is accelerated by the chronic hyperglycemic state, the microvascular disturbance is caused to result in diabetic neuropathy.
On the other hand, in the disturbed metabolism theory, the causes thereof can be classified into a group of the activation of the polyol metabolic pathway and the non-enzymatic protein glycosylation, It is commonly accepted that both vascular dysfunction theory and disturbed metabolism theory are correct. Also, it is considered that the disturbed metabolism mainly causes the initial stage of the diabetic neuropathy and, as the disease reaches an advanced stage, the concern of the-vascular dysfunction increases.
Epalrestat [Japanese Patent Unexamined Published Application (hereinafter referred to as “J. P. KOKAI”) No. Sho 57-40478; EP 47109A] which is an aldose reductase inhibitor effective in inhibiting the activation of the polyol metabolic pathway is used as a remedy for diabetic neuropathy. However, this remedy is not so effective and is unsatisfactory for curing the human disease, while the symptoms of animals can be almost completely recovered with it. Reasons for this phenomenon are, for example, that the effects of this remedy vary depending on the species and that the amount of the aldose reductase varies among the patients.
Under these circumstances, not only remedies developed on the basis of the disturbed metabolism theory but also remedies developed on the vascular dysfunction theory are being developed. It is known that vasodilators such as &agr;1 receptor antagonists, angiotensin receptor antagonists, angiotensin converting enzyme inhibitors, calcium channel blockers, endothelin receptor antagonists, prostaglandin preparations and nitric oxide donors inhibit the neuropathy of streptozotocin induced diabetic rats or they even improve the neuropathic symptoms. However, most of these vasodilators have a blood pressure-lowering effect which is undesirable for the patients with diabetic neuropathy.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a pharmaceutical composition for use in the treatment of diabetic neuropathy.
After intensive investigations made with diabetes model rats, the inventors have found that specified piperidine derivatives disclosed in J. P. KOKAI No. Hei 8-3135 and known as serotonin antagonists or antithrombocytic agents having an effect of inhibiting the platelet aggregation have an extremely high curative effect on diabetic neuropathy when they are used in such a dose that they do not cause the lowering of the blood pressure. The present invention has been completed on the basis of this finding.
Namely, the present. invention relates to a pharmaceutical composition for use in the treatment of diabetic neuropathy, which comprises a piperidine derivative represented by the following general formula (1) or a salt thereof as an effective ingredient:
wherein n is an integer of 2 or 3, Y is a hydrogen atom or halogen atom, and X is a formyl group, acetyl group or hydrogen atom.
There is also provided a method for the treatment of diabetic neuropathy which comprises the step of administering an effective amount of a piperidine derivative represented by the following general formula (1) or a salt thereof to a patient with diabetic neuropathy.
The compounds of the present invention are particularly effective when diabetic neuropathy is caused by a microvascular circulatory disturbance and particularly when the microvascular circulatory disturbance therein is caused by accelerated platelet aggregation. In the compounds of general formula (1) in the present invention, a compound of the formula wherein n is 2, Y is a hydrogen atom and X is a formyl group is particularly effective.
REFERENCES:
patent: 5932593 (1999-08-01), Makino et al.
patent: 8-003135 (1996-01-01), None
Cameron Norman E.
Kihara Hideaki
Yoshimoto Ryota
Ajinomoto Co. Inc.
Krass Frederick
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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